Human apolipoprotein E (apoE) consists of a single polypeptide chain with 299 amino acids and is best known for its role in the transport of cholesterol and other lipids between peripheral tissues and the liver. However, more direct effects of apoE on the vascular wall may well contribute to arterial protection from atherosclerosis. This review will focus on: (a) the ability of apoE to direct cholesterol efflux mechanisms with the aid of apoA1 and the ATP binding cassette transporter 1 (ABC1); (b) the ability of apoE to prevent platelet aggregation by facilitating the production of endogenous nitric oxide (NO); (c) the ability of apoE to inhibit the proliferation of T-lymphocytes by internalization of the IL-2 receptor; and (d) the ability of apoE to inhibit proliferation of endothelial cells by out competing growth factors for interaction with cell surface heparan sulfate proteoglycans (HSPG's). The characterization of apoE and its many functions has provided insight into the ultimate potential of this protein as a possible therapeutic agent for the treatment of atherosclerosis. This review will examine key scientific advances, which focus on possible therapeutic strategies that encompass the use of apoE in the amelioration of atherosclerosis.